T cell-mediated Immunity Flashcards
Can gammadelta T cells recognize non MHC bound antigens?
No, they bind to peptides/molecules presented on MHC-like proteins
How is CD8/CD4 switched off during T cell maturation?
Both CD4 and CD8 are initially expressed during the “testing” stage and if the CD8 is activated as the coreceptor it stays that way and CD4 is removed and vice versa.
How do microbes end up inside cells?
A: Microbes enter through phagocytosis by surviving inside and escaping into cytoplasm
B: Viral binding of receptors and entry into cytoplasm
What other functions do T cells do in addition to defense against intracellular pathogens?
T lymphocytes are important for defense against larger extracellular pathogens like bacteria, fungi, and helminths.
The subset of CD4 cells that do this were unknown when classic role of T cells was first defined. A major role of these subsets is to help B cells produce antibodies. Another role is to promote inflammation that is rich in activated leukocytes that are particularly efficient at killing extracellular microbes.
Potential short answer questions on the exam:
The signals needed to activate T lymphocytes, and cellular receptors used to
sense and respond to these signals
– How the few naive T cells specific for any microbe gets converted into large
number of effector T cells that have specialised functions and ability to eliminate
diverse microbes?
– The molecules produced by T lymphocytes that mediate their communications
with other cells, such as macrophages, B lymphocytes, and other leukocytes?
What are the 3 phases of T cmi?
Induction of response: Naive CD4+ T cells and CD8+ T cells recognise peptide antigens presented by APCs in peripheral lymphoid organs. T cells proliferate and differentiate into effector cells.
Migration of effector T cells and other leukocytes to site of antigen
T cell effector functions
How are activated T cells guided to the site of the antigen?
Effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues
What are the T cell effector functions?
CD4+ T cells recruit and activate phagocytes to destroy microbes
CD8+ cytotoxic T cells kill infected cells and can also activate macrophages
What are the 3 critical stimuli for full T cell activation?
Antigen recognition initiates process
Co-stimulation maximises response
Cytokines amplify response and direct it along various specialised differentiation pathways
What are the phases of T cell response?
Antigen recognition, activation and cytokine secretion.
Some cytokines stimulate proliferation of antigen-activated T cells (clonal expansion) and differentiation into effector T cells.
What does IL-2 do?
Acts on itself to stimulate proliferation/clonal expansion.
IL-2 is also known as a T Cell growth factor
What can T cells differentiate into?
Effector T cells (CD4+ helper)
Memory T cell
Where do effector T cells go after being activated?
Many leave lymphoid organs through blood and migrate to infected tissue and eradicate microbes while others provide signals to B cells that promote antibody responses against microbes.
What receptors and membrane proteins are involved in binding of MHCII and T cell activation?
TCR binds to peptide+MHCII
CD4 - MHCII invariant region
Zeta chain and CD3 bind closely to TCR forming the TCR complex
LFA-1 binding ICAM-1 (same as neutrophil and extravasion)
CD28 binding B7-1/B7-2
What membrane proteins are important for T cell adherence to endothelium?
VLA-4 binding VCAM-1
What are superantigens?
Polyclonal activators of T cells that activate many different T cells.
What kind of problem can superantigens lead to?
Systemic inflammatory disease due to excessive production of cytokines from many T cells.
Why is low affinity selected for with TCRs?
Adhesion molecules on T cells recognize ligands on APCs and stabilise binding of T cells to APCs for long enough for signalling threshold to be achieved.
What is LFA-1 and what does it bind to?
Leukocyte function-associated antigen 1 (LFA-1) which binds to ICAM-1. (IntraCellular Adhesion Molecule 1)
What family of proteins is LFA-1 associated with?
Heterodimeric (2-chain) proteins known as integrins
What receptors are important for co-stimulation of T cells?
Best-defined co-stimulators for T cells are B7-1 (aka CD80) and B7-2 (aka CD86) which bind to CD28 on all T cells.
Which cells have CD28?
Virtually all T cells
Which cells have B7 receptors (aka CD80 and CD86)?
T cells, B cells, dendritic cells, macrophages.
APCs in general.
What happens during co-stimulation?
APC presents antigen on MHCII (via TCR and CD4) in addition to this there must be binding between B7-1/2 and CD28 which results in activation of T cell and in return IL-12 is produced which activates T cell and allows it to proliferate and differentiate.
How do adjuvants help with creating immune memory?
They induce expression of co-stimulators on APCs and stimulate secretion of cytokines.
It boosts activation of Pattern Recognition Receptors (PRRs such as TLRs) activation by administering microbes or microbe like molecules.
They trick immune system into responding to purified protein antigens.
What does artificially blocking co-stimulation help with?
Agents that block B7:CD28 are used to treat rheumatoid arthritis, inflammatory disease and graft rejections.
Antibodies blocking CD40:CD40L are being tested in inflammatory diseases and transplant recipients.
What use is there for co-stimulation in the immune system?
Co-stimulators provide an opportunity for the body to regulate activation of T cells with homologous proteins to CD28.
What is CTLA-4?
A prototype of inhibitory receptors for B7-1 ad B7-2 on APCs.
What is PD-1?
An inhibitory receptor that recognizes different but structurally related ligands on many cell types.
When are CTLA-4 and PD-1 induced?
In activated T cells. They provide negative feedback for the growth and proliferation of T cells. (inhibition of these in mice cause lymphocyte expansion and autoimmune disease)
What important function do CTLA-4 and PD-1 have besides regulation of proliferation?
They inhibit responses to tumours.
PD-1 inhibits responses to some chronic viral infections (blocking CTLA-4 or PD-1 is used to enhance immune responses to tumours)
How are CD8 T cells activated?
Recognition of MHCI (may also require CD4+ helper T cells)
Costimulation
Which phenomenon is explained by the action of CD4 on CD8 T cells?
The diminished immune response seen in HIV patients.
What happens to T cells after activation?
Accumulation of biochemical responses which result in elevated protein synthesis and expression of various signalling molecules (IL-2, IL-2 receptor, CD69, CD40 ligand, c-Fos)
What happens at the immunological synapse?
Tight binding for a brief amount of time and an orderly redistribution of proteins in both APCs and T cell membranes at point of cell-to-cell contact.
What does IL-2 do?
Autocrine growth stimulator
What is the sequence of events that take place following receptor activation? (the signal transduction pathway)
Lck bound to CD4/CD8 receptor which instigates phosphorylation of CD3 zeta - ITAM regions.
ZAP-70 then comes in and docks onto CD3 Zeta chain and binds to the phosphorylated ITAM part of CD3-zeta.
ZAP70 then activates phosphorylation events of various adapter proteins and enzymes that assemble near TCR complex.
One adapter protein, PLCγ1, activates the NFAT pathway and PI3-kinase activates mTOR which activates AP-1 and NFκB.
Zap-70 and zeta pathway activates several pathways. What are these pathways?
Calcium-NFAT pathway
Ras and Rac-MAP kinase pathways
PKCθ-NFκB pathway
PI3-kinase pathway
What is the NFAT pathway?
A pathway that is triggered by an increase in cytosolic calcium. This pathways activates several genes including genes encoding T cell growth factor IL-2 and components of IL-2 receptor.
What drug uses the NFAT pathway as a target to suppress the immune system?
Cyclosporine
What does the PI3-Kinase pathway do?
A pathway that stimulates expression of anti-apoptotic proteins promoting survival of antigen stimulated T cells.
What pathway is stimulated by phosphatidyl-inositol3 kinase?
Akt - mTOR which increases protein synthesis.
What drug inhibits the PI3-kinase pathway?
Rapamycin which targets the mTOR pathway
What are the functional responses of T cells to antigens and co-stimulation?
Cytokine release act on T cells and other cells involved in immune defenses. Cytokines function as mediators of immunity and inflammation.
What does IL-2 do?
Promotes survival, proliferation and differentiation of effector and regulatory T cells.
What cells produce IL-2?
CD4 and CD8 T cells (activated CD8+ T cells don’t appear to produce large amounts of IL-2 but they do proliferate)
What does IL-4 do?
B cell switching to IgE
What cells produce IL-4?
CD4 and mast cells
What does IL-5 do?
Activates eosinophils
What cells produce IL-5?
CD4 T cells and mast cells
What does IFN-γ do?
Activates macrophages
what cells produce IFN-γ?
CD4 CD8 and NK cells
What does IL-17 do?
Stimulates acute inflammation
What cells produce IL-17?
CD4 CD8 and NK cells
What does TGF-β do?
Inhibits T cell activation and differentiation of regulatory T cells
What cells produce TGF-β?
CD4 T cells mainly and many other cell types
When is IL-2 produced?
First produced within 1 - 2 hours after activation of the T cell
What does activation do to affinity of IL-2 receptor?
It enhances the affinity of the cell for IL-2 by increasing production of IL-2R for strong binding.
What kind of signalling molecule is IL-2?
Mostly an autocrine cytokine
Why are CD8 T cells produced more rapidly than CD4 T cells?
Because CD8 T cells are important for actual killing of infected cells whereas CD4 T cells produce lots of cytokines without doing any killing
What are the types of memory cells?
Central memory cells which populate lymphoid organs and are responsible for rapid clonal expansion after re-exposure to antigen.
Effector memory cells localise in mucosal and other peripheral tissues that are essentially effector cells which can act rapidly on reinfecting antigens
